Ph.D. Thesis
Title Polymers and Block Copolymers of Isocyanopeptides-Towards
Higher Structural Order in Macromolecular Systems
Adviser Prof. Dr. R.J.M. Nolte
Thesis Committee Prof. Dr. Steggerda (chairman), Dept. of Inorganic
Chemistry, University of Nijmegen; Dr. N.A.J.M. Sommerdijk (co-adviser),
Prof. Dr. E.W. Meijer, Dr. A.P.J.H. Schenning, Lab. of Macromolecular
and Organic Chemistry, Eindhoven University of Technology; Dr. P.C.J.
Kamer, Dept. of Inorganic Chemistry and Homogeneous Catalysis, University
of Amsterdam; Prof. Dr. E. Vlieg, Dept. of Solid State Chemistry,
University of Nijmegen; Prof. Dr. C.W. Hilbers, Dept. of Physical
Chemistry, University of Nijmegen; Prof. Dr. F.P.J.T. Rutjes, Dept.
of Organic Chemistry, University of Nijmegen; and Dr. A.E. Rowan,
Dept. of Organic Chemistry,University of Nijmegen.
Essay
Since van 't Hoff and Le Bel independently proposed
the concept of the tetrahedral carbon geometry, stereochemistry has
been a key element in not only the chemical diciplines, but also in
related areas in biology, physics and materials science. On the molecular
level stereochemistry provides the parameters by which we understand
the properties of a substance, the way information is transferred
in biological systems and other processes essential in life. The importance
of (controlling) molecular geometry is recently emphasized again by
awarding the 2001 Nobel Prize in chemistry to catalytic asymmetric
synthesis.
Stereochemistry in man-made polymeric materials, however,
remained an unexplored area untill the development of the Ziegler
catalysts and the pioneering work of Natta and Pino on stereoregularity
and optical activity in polyolefins. More recently the elegant studies
by Green and others on optically active helical polymers have shown
the versatility of these kind of systems and the analogy they display
with (the formation of) structural motifs in proteins. In synthetic
macromolecules, however, no transfer of stereochemical or structural
information from the monomer level to a defined polymeric architecture
and subsequently to an ordered assembly of macromolecules, like is
present in biopolymers, has been observed to date. The investigations
presented in my thesis, deal with this hierarchical transfer of stereochemical
information (i.e. chirality) present in monomeric peptide related
isocyanides to higher levels of molecular organization, i.e.
in polymers and block copolymers of these isocyanides and in aggregates
formed by them. Polyisocyanides have a rather well defined helical
conformation and are accessible in an optically active form by a nickel
catalyzed polymerization reaction. This macromolecular 41 helix
(side chain n is more or less above side chain n + 4)
is stable in solution when bulky side groups are present, but slowly
unfolds in the case of less stericly demanding side groups.
In the first part of my thesis the synthesis, characterization
and conformational studies on polymers of isocyanopeptides are described.
Because of the regular helical structure it was proposed that hydrogen
bonds could be formed between the amide groups present in the side
chains which are more or less above each other. This would result
in an increased regularity, stability and rigidity of the macromolecular
helix. Using the single crystal X-ray structure of one of the monomers
as a reference, infrared (IR) and 1H NMR studies revealed
that indeed such a hydrogen bonding pattern is present between the
side groups n and n + 4. Due to a sort of preorganizing effect of
the monomers a highly organized polymer is formed which is even more
rigid than DNA and, depending on the composition of the side arms,
stable at elevated temperatures (i.e. 40-50 �C) above which
they unfold in a co-operative fashion. These conclusions were established
by a host of experiments combining Circular Dichroism (CD) spectroscopy,
X-ray scattering and model calculations. Because of the rigid character
of the polymers it was possible to visualize individual macromolecules
by Atomic Force Microscopy (AFM), which also enabled us to determine
their absolute molecular weights.
Expanding the size of the side chains in the polyisocyanopeptides
from a di- to a tripeptide, results in the formation of polymers with
a beta-sheet-like organization of these side groups. The macromolecular
architecture obtained in this way mimics the beta-helical structural
motif found in proteins and can act as a reference point in the study
of amyloid fibers. The straightforward chemical transformation of
the penultimate methyl esters of the side groups to carboxylates led
to the formation of watersoluble macromolecules. From IR spectroscopy
and the slow H/D exchange observed in the 1H NMR experiment is was
concluded that hydrogen bonds are still present in water, both in
the di- and tripeptide case. This shows the highly efficient side
chain directing capacity of the macromolecular helix; achieving ordered
hydrogen-bonded architectures in water has appeared to be notoriously
difficult in the past. In particular without the protection of the
hydrogen bonding groups from the solvent, for example by the creation
of a hydrophobic pocket.
Although the polyisocyanopeptides soluble in organic
solvents formed cholesteric lyotropic liquid crystalline phases in
concentrated solutions, we aimed for the formation of defined asymmetric
structures by self-organizing chiral block copolymers in an aqueous
environment. For this purpose block copolymers were synthetisized
containing a hydrophobic polystyrene segment and a helical, charged
polyisocyanide part. Under optimized conditions these superamphiphiles
self-assembled in water, like low molecular weight surfactants do,
to form a variety of structures (e.g. micelles, rods, plates
and vesicles). When the relative ratio of the hydrophilic and hydrophobic
parts is small also helical superstructures were observed. The mechanism
of formation of these superhelices is dependent on the chemical nature
of the side groups, but more interestingly involves the hierarchical
transformation of chiral information present in the monomer via the
macromolecular conformation to the superhelix formed. In this way
providing the first example of the formation of asymmetric architectures
by the self-assembly of amphiphilic block copolymers.
In the final part of my thesis the synthesis and aggregation
behavior of block copolymers containing a unique combination of structural
elements, i.e. a flexible, bulky and apolar dendritic carbosilane
segment and a rigid, helical rod-like polyisocyanopeptide block, is
described. The solubility parameters of the resultant macromolecules
were different from the homopolymers, but to obtain larger ordered
aggregates silver salts were added to increase the incompatibility
between the component blocks. It was found that depending on the volume
fraction of the two polymer segments micellar assemblies were formed.
In the presence of silver larger structures were formed which deposited
on a surface in a striping pattern consisting of metal rich and poor
domains. Remarkably, under the influence of the electron beam in the
Transmission Electron Microscope (TEM) the silver salts were reduced
and metallic silver nanopatterns were formed.
Because of the defined architecture and the hierarchical
organization displayed by the polyiscocyanopeptides described in my
thesis, these macromolecules with tunable properties can be considered
as synthetic analogs of naturally occuring proteins (e.g. beta-sheet
helices) and serve as reference points in the study of complex assembling
processes.